6/10/2003 @ 7:00AM

Genentech's Next Move

Genentech
stunned the cancer world last week with news that its Avastin colon cancer drug extended patients’ lives by five months, proving wrong skeptics who said the blood vessel-blocking drug would never work. Now the biotech pioneer is embarking on a bold strategy to dominate the cancer drug market for decades to come by combining drugs even before they are approved.

Genentech
Historically, new cancer drugs are tested one at a time, which allows for the types of clear statistical comparisons between drugs that regulators like. But this plodding approach means it can take years and sometimes even decades to tease out the most effective cancer drug combinations.

In a risky gambit to speed the development of breakthroughs, the South San Francisco biotech firm is planning to test combinations of multiple experimental cancer drugs simultaneously in new tumor types, instead of waiting for each one to be approved separately before combining them. The hope is that slamming multiple defective genes at once with highly targeted drugs will increase the chance of long-lasting remissions or even cures.

“It’s one plus one equals three,” says Genentech
Vice President
Gwen
Fyfe
Gwen Fyfe
, who oversees the company’s cancer trial program. “Cancer cells have a lot of redundant systems, and in order to actually kill a cell you may need to block a defective pathway in multiple ways.” Even though each drug alone may not stop the cancer, “you put them together and you may kill the tumor cell,” she explains. Ultimately, the hope is that relatively gentle new combinations of gene-targeted drugs will be able to replace far more toxic chemotherapy regimens.

Genentech is buoyed by preliminary results of a small lung-cancer trial conducted by M.D. Anderson Cancer Center’s
Roy
Herbst
Roy Herbst
and Vanderbilt-Ingram Cancer Center’s
Alan
Sandler
Alan Sandler
. The trial combines Avastin with Genentech’s experimental drug Tarceva, which is being developed with
OSI Pharmaceuticals
. Tarceva, which is similar to
AstraZeneca
‘s
Iressa, has shrunk tumors in roughly 10% of lung cancer patients when used as a single agent; Avastin by itself generally has not shrunk lung tumors.

But when the two drugs were combined in 12 patients with advanced lung cancer, tumors shrunk in 25% of the patients and stabilized in another 40%–much more impressive results than the two drugs produce alone. The reason for the synergy may lie in the drugs’ complementary mechanisms. Tarceva blocks epidermal growth factor (EGF) receptor, a growth-promoting protein that is overabundant in many tumors, while Avastin hits vascular endothelial growth factor (VEGF), which tumors use to grow blood vessels.

Lab evidence indicates that an overactive EGF system may help tumors produce more VEGF. The trial is continuing to enroll more patients, and if the full trial shows similar results, Genentech may begin larger trials. Another early-stage trial is combining Tarceva and Avastin in colon cancer patients.

Genentech is in a particularly strong position to test new drug combinations because it has so many gene-targeted cancer drugs in its portfolio. In addition to Tarceva and Avastin, it sells the breast cancer drug Herceptin, which targets a gene called Her-2 that is defective in about 25% of breast cancer patients. Ongoing trials are testing Herceptin in combination with Tarceva in advanced breast cancer. Separately, Genentech is doing early-stage testing of 2C4, a drug that works by a novel mechanism to simultaneously disrupt both Her-2 and EGF in a variety of tumor types.

Genentech will have to work quickly to stay ahead of the competition. Its anti-EGF drug Tarceva will have to compete with AstraZeneca’s Iressa in fighting lung cancer, as well as Erbitux from
ImClone Systems
and
Bristol-Myers Squibb
, used against in colon cancer. Moreover, numerous drug firms are jumping on the multi-gene approach and testing drugs that hit several bad cancer genes at once.
Pfizer
, for example, is testing SU11248, which blocks VEGF and several other bad genes. Researchers reported at the recent American Society of Clinical Oncology cancer conference that SU11248 shrank a number of patients’ tumors in several very preliminary studies.